Anti-rsv monoclonal antibody formulation

ABSTRACT

The present invention provides a formulation comprising: (i) an anti-RSV monoclonal antibody; and (ii) an ionic excipient; wherein the monoclonal antibody is present at a concentration of about 50 mg/ml or greater and the ionic excipient is present at a concentration of between 50 and 150 mM and the formulation has a pH of about 5.5 to about 7.5.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of U.S. Provisional Application Ser.No. 62/465,379, filed Mar. 1, 2017, which is incorporated by referenceherein.

SEQUENCE LISTING

This application contains a Sequence Listing electronically submittedvia EFS-Web to the United States Patent and Trademark Office as an ASCIItext file entitled “490-00050101_ST25.txt” having a size of 12 kilobytesand created on Feb. 28, 2018. The information contained in the SequenceListing is incorporated by reference herein.

FIELD OF THE INVENTION

The invention is concerned with an anti-RSV antibody formulation, inparticular, an anti-RSV monoclonal antibody formulation and usesthereof. The invention also is concerned with an isolated anti-RSVmonoclonal antibody and uses thereof.

BACKGROUND OF THE INVENTION

Respiratory Syncytial Virus (RSV) is a common cold virus belonging tothe family of paramyxovirus. RSV is virulent, easily transmissible andthe most common cause of lower respiratory tract disease in children ofless than 2 years of age. Up to 98% of children attending day care willbe infected in a single RSV season. Between 0.5%> and 3.2% of childrenwith RSV infection require hospitalization. Approximately 90,000hospital admissions and 4,500 deaths per year were reported in UnitedStates. Major risk factors for hospitalization due to RSV are prematurebirth, chronic lung disease, congenital heart disease, compromisedimmunity, and age younger than 6 weeks in otherwise healthy children,There is a need for additional treatment for RSV positive bronchiolitisbeside supportive care in the form of adequate nutrition and oxygentherapy. Antiviral therapies such as Ribavirin have not been proven tobe effective in RSV infection. One monoclonal antibody, Palivizumab(also called Synagis<®>), is registered for prophylaxis against RSVinfection. Palivizumab is a genetically engineered (humanized)monoclonal antibody to the fusion protein of RSV. While Palivizumab hasbeen a very effective prophylactic, alternative antibodies and therapiesproviding additional coverage against RSV would be advantageous.

As a result of the isoelectric point (pI) of a number of anti-RSVmonoclonal antibodies being in the preferred pharmaceutical pHformulation range for proteins (pH 5.5 to pH 7.5), these moleculespresent unique formulation challenges.

Colloidal instability at a molecules pI is due to a lack of anelectrostatic charge on the molecule, which allows closerprotein-protein interactions (so-called “self-association”) that lead tophysical instabilities. For this reason, the pH of a protein formulationis typically selected to be at least 1 pH unit away from the protein pI.This aims to provide colloidal stability and thus prevent the physicalinstabilities, such as aggregation, precipitation, opalescence, phaseseparation and/or particle formation.

According to the ‘1 pH unit away’ rule, antibodies having a low orneutral pI e.g. pI of pH 5.5 to pH 7.5 thus should be formulated into aformulation with a pH outside the range of 5.5 to 7.5. However, outsidethis range, additional instabilities can be observed. At more acidic pH,an increased rate of fragmentation reduced conformational stability andincreased aggregation can be observed. At more basic pH, the potentialfor increased oxidation, deamidation and fragmentation andincompatibility with glass containers are present.

The above instabilities are particularly problematic in such anti-RSVantibody formulations where the antibody is present at a commerciallydesirable concentration e.g. 50 mg/ml and above.

Therefore, there exists a need to provide an improved formulation for ananti-RSV antibody having a low or neutral pI. In particular, thereexists a need to provide a stable formulation for an anti-RSV antibodyhaving a low or neutral pI and, particularly such a formulation having acommercially desirable antibody concentration.

BRIEF SUMMARY OF THE INVENTION

The present invention provides a new anti-RSV antibody formulation, inparticular a new anti-RSV monoclonal antibody formulation. Inparticular, the present formulation provides a means for improvingcolloidal stability for antibodies having a low or neutral pI. Thepresent invention thus provides an alternative to the ‘1 pH away’ rulefor providing colloidal stability. The present invention thus allowsantibodies having a low or neutral pI to be formulated within 1 pH unitof the antibody pI. Thus, the present invention enables such antibodiesto be formulated within a pH range of 5.5 to 7.5 and at a commerciallyuseful concentration, whilst substantially avoiding the instabilitiesassociated with more acidic or more basic pHs.

The present invention further provides a new anti-RSV antibody MEDI8897.An improved pharmaceutically suitable formulation of the new anti-RSVantibody MEDI8897 is facilitated by formulating the antibody accordingto the teaching of the present invention.

The invention is particularly concerned with anti-RSV antibodies havinga low or neutral pI, in particular the MEDI8897 antibody. MEDI8897 is ahuman IgG1κ- YTE monoclonal antibody directed against RSV-F protein.

MEDI8897 has a full length heavy chain sequence of FIG. 1 (SEQ ID NO: 2)and a full length light chain sequence of FIG. 2 (SEQ ID NO: 1).

MEDI8897 has CDR sequences: light chain CDR-L1 of QASQDIVNYLN (SEQ IDNO: 3), light chain CDR-L2 of VASNLET (SEQ ID NO: 4), light chain CDR-L3of QQYDNLPLT (SEQ ID NO: 5), heavy chain CDR-H1 of DYIIN (SEQ ID NO: 6),heavy chain CDR-H2 of GIIPVLGTVHYGPKFQG (SEQ ID NO: 7), and heavy chainCDR-H3 of ETALVVSETYLPHYFDN (SEQ ID NO: 8). The 6 CDRS are underlined inFIGS. 1 and 2.

MEDI8897 has a light chain variable sequence of amino acid residues 1 to107 of FIG. 1 (SEQ ID NO: 9) and a heavy chain variable sequence ofamino acid residues 1 to 126 of FIG. 2 (SEQ ID NO: 10).

MEDI8897 pI was measured by cIEF to be 6.4 to 6.7, with the main peak at6.4. The pI thus overlaps with the desired pharmaceutical formulationbuffer range and suggests potential issues with manufacturing,formulation and storage stability if formulated within this range.

The invention provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody; and    -   ii. an ionic excipient;        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml) and the ionic excipient is present at a concentration of        about 50 to 150 mM and the formulation has a pH of about 5.5 to        about 7.5.

In one embodiment, the anti-RSV monoclonal antibody has a low or neutralpI, for example in the range about pH 5.5 to about pH 7.5. In oneembodiment, the monoclonal antibody has a pI in the range of about pH6.0 to about pH 7.5. In one embodiment, the monoclonal antibody has a pIin the range of pH about 6.3 to about pH 7.5. In one embodiment, themonoclonal antibody has a pI in the range of about pH 6.4 to about pH7.5. In one embodiment, the monoclonal antibody has a pI in the range ofabout pH 6.4 to about pH 6.7. In one embodiment, the monoclonal antibodyhas a pI of about pH 6.4. Without wishing to be bound by theory, a lowto neutral pI can occur for proteins where there is a either a netbalance of oppositely charged (positive amine groups and negativecarboxylate groups) amino acid side chains on the protein or differentdomains have overall oppositely charge, within a pH range of about 5.5to about 7.5. Again, without wishing to be bound by theory, it ispossible that the ionic excipient in the formulation of the inventionshields these opposing and attractive charges, thus colloidallystabilizing proteins having a pI within this range. The presentinvention thus provides use of an ionic excipient in an antibodyformulation for the purpose of changing the charge state or distributionof the antibody in the formulation. The present invention furtherprovides use of an ionic excipient in an antibody formulation for thepurpose of colloidally stabilizing the antibody in the formulation.

In one embodiment, the monoclonal antibody is present in theformulations described herein at a concentration of about 75 mg/ml orgreater (e.g., about 75 mg/ml to about 200 mg/ml). In one embodiment,the monoclonal antibody is present in the formulations described hereinat a concentration of about 100 mg/ml or greater. In one embodiment, theanti-RSV monoclonal antibody is present in the formulations describedherein at a concentration of about 100 mg/ml to about 165 mg/ml. In oneembodiment, the anti-RSV monoclonal antibody is present at aconcentration of about 100mg/ml. In one embodiment, the ionic excipientis present at a concentration of about 75 mM to about 100 mM. In oneembodiment, the ionic excipient is present at a concentration of about75 mM. In one embodiment, the ionic excipient is present at aconcentration of about 80 mM.

In one embodiment, the monoclonal antibody is an IgG1 monoclonalantibody. The invention thus provides a formulation comprising:

-   -   i. an IgG1 anti-RSV monoclonal antibody; and    -   ii. an ionic excipient;        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml) and the ionic excipient is present at a a concentration        of about 50 to about 150 mM and the formulation has a pH of        about 5.5 to about 7.5.

In one embodiment, the formulations described herein have a pH in therange of about pH 5.5 to about pH 6.5. In one embodiment, theformulations described herein have a pH in the range of about pH 5.7 toabout pH 6.3. In one embodiment, the formulations described herein havea pH in the range of about pH 5.7 to about pH 6.1. Preferredformulations have a pH of about 5.8. Other preferred formulations have apH of about 6.0.

In one embodiment, the ionic excipient is a charged amino acid. In oneembodiment, the ionic excipient is lysine. In another embodiment, theionic excipient is arginine.

In one embodiment, the ionic excipient is a salt. The invention thusprovides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody as defined anywhere herein;        and    -   ii. a salt;        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater and the salt is present at a        concentration of about 50 to about 150 mM and the formulation        has a pH of about 5.5 to about 7.5.

In one embodiment, the salt is present at a concentration of about 75 mMto about 100 mM. In one embodiment, the salt is present at aconcentration of about 75 mM or about 80 mM.

In one embodiment, the salt is arginine hydrochloride, for example at aconcentration of about 75 mM to about 100 mM, suitably at aconcentration of about 80 mM.

In one embodiment, the formulation further comprises a sugar. Amongstother known benefits, the presence of a sugar can improve tonicity ofthe formulation. This is desirable since preferred formulations areisotonic or near isotonic. In one embodiment, the ionic excipient is asalt and the formulation further comprises a sugar.

The invention thus provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody as defined anywhere herein;    -   ii. an ionic excipient (e.g. a salt) as defined anywhere herein;    -   iii. a sugar as defined anywhere herein; and        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater and the ionic excipient is present at        a concentration of about 50 to about 150 mM and the formulation        has a pH of about 5.5 to about 7.5.

In one embodiment, the formulation further comprises a sugar and theionic excipient is present at a concentration in the range of about 75mM to less than 150 mM. In one embodiment, the formulation furthercomprises a sugar and the ionic excipient is present at a concentrationin the range of about 75 mM to about 100 mM. In one embodiment, theformulation further comprises a sugar, which is present at aconcentration in the range of about 100 mM to about 140 mM, and theionic excipient is present at a concentration in the range of about 75mM to about 100 mM.

In one embodiment, the sugar is sucrose, for example at a concentrationof about 100 mM to about 140 mM, suitably at a concentration of about120 mM.

In one embodiment, the formulation further comprises one or morebuffers. In one embodiment, the one or more buffers is a buffercomprising histidine. In one embodiment, the one or more buffers areselected from a buffer comprising histidine succinate, histidineacetate, histidine citrate, histidine chloride or histidine sulfate. Inone embodiment, the one or more buffers is histidine, histidinehydrochloride, or a combination thereof (histidine/histidinehydrochloride). In one embodiment, the one or more buffers isL-histidine/L-histidine hydrochloride monohydrate, for example at aconcentration of about 10 mM to about 50 mM, suitably at a concentrationof about 30 mM. It will be understood that a buffer may, itself, be anionic excipient. Thus, in one embodiment, the buffer is the ionicexcipient. In this embodiment, the concentration of the buffer should beabove 50 mM i.e. in line with the concentration of the ionic excipientdisclosed herein. Put another way, in one embodiment, the ionicexcipient also acts as a buffer in the formulation. In this embodiment,an additional buffer may or may not be present.

In one embodiment, the formulation further comprises a surfactant. Inone embodiment, the surfactant is a polysorbate, including for example,polysorbate-80.

In one embodiment, the formulation further comprises a sugar and one ormore buffers. In one embodiment, the ionic excipient is a salt and theformulation further comprises a sugar and one or more buffers.

In one embodiment, the formulation further comprises a surfactant, asugar and one or more buffers. In one embodiment, the ionic excipient isa salt and the formulation further comprises a surfactant, a sugar andone or more buffers.

The invention thus provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody as defined anywhere herein;    -   ii. an ionic excipient (e.g. a salt) as defined anywhere herein;    -   iii. a sugar as defined anywhere herein;    -   iv. one or more buffers as defined anywhere herein; and    -   v. optionally a surfactant as defined anywhere herein        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater and the ionic excipient is present at        a concentration of about 50 to about 150 mM and the formulation        has a pH of about 5.5 to about 7.5.

The invention also provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody having a heavy chain variable        region CDR1 sequence comprising a sequence which is at least 70%        identical to the heavy chain variable region CDR1 sequence of        MEDI 8897, and a heavy chain variable region CDR2 sequence        comprising a sequence which is at least 70% identical to the        heavy chain variable region CDR2 sequence of MEDI 8897, and a        heavy chain variable region CDR3 sequence comprising a sequence        which is at least 70% identical to the heavy chain variable        region CDR3 sequence of MEDI 8897, and a light chain variable        region CDR1 sequence comprising a sequence which is at least 70%        identical to the light chain variable region CDR1 sequence of        MEDI 8897, and a light chain variable region CDR2 sequence        comprising a sequence which is at least 70% identical to the        light chain variable region CDR2 sequence of MEDI 8897, and a        light chain variable region CDR3 sequence comprising a sequence        which is at least 70% identical to the light chain variable        region CDR3 sequence of MEDI 8897;    -   ii. an ionic excipient (e.g. a salt) as defined anywhere herein;    -   iii. a sugar as defined anywhere herein;    -   iv. one or more buffers as defined anywhere herein; and    -   v. optionally a surfactant as defined anywhere herein        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml) and the ionic excipient is present at a a concentration        of about 50 to about 150 mM and the formulation has a pH of        about 5.5 to about 7.5. In one embodiment, the anti-RSV        monoclonal antibody has a heavy chain variable region CDR1        sequence comprising a sequence which is at least 80% identical        to the heavy chain variable region CDR1 sequence of MEDI 8897,        and a heavy chain variable region CDR2 sequence comprising a        sequence which is at least 80% identical to the heavy chain        variable region CDR2 sequence of MEDI 8897, and a heavy chain        variable region CDR3 sequence comprising a sequence which is at        least 80% identical to the heavy chain variable region CDR3        sequence of MEDI 8897, and a light chain variable region CDR1        sequence comprising a sequence which is at least 80% identical        to the light chain variable region CDR1 sequence of MEDI 8897,        and a light chain variable region CDR2 sequence comprising a        sequence which is at least 80% identical to the light chain        variable region CDR2 sequence of MEDI 8897, and a light chain        variable region CDR3 sequence comprising a sequence which is at        least 80% identical to the light chain variable region CDR3        sequence of MEDI 8897. In one embodiment, the anti-RSV        monoclonal antibody has a heavy chain variable region CDR1        sequence comprising a sequence which is at least 90% identical        to the heavy chain variable region CDR1 sequence of MEDI 8897,        and a heavy chain variable region CDR2 sequence comprising a        sequence which is at least 90% identical to the heavy chain        variable region CDR2 sequence of MEDI 8897, and a heavy chain        variable region CDR3 sequence comprising a sequence which is at        least 90% identical to the heavy chain variable region CDR3        sequence of MEDI 8897, and a light chain variable region CDR1        sequence comprising a sequence which is at least 90% identical        to the light chain variable region CDR1 sequence of MEDI 8897,        and a light chain variable region CDR2 sequence comprising a        sequence which is at least 90% identical to the light chain        variable region CDR2 sequence of MEDI 8897, and a light chain        variable region CDR3 sequence comprising a sequence which is at        least 90% identical to the light chain variable region CDR3        sequence of MEDI 8897. In one embodiment, the anti-RSV        monoclonal antibody has a heavy chain variable region CDR1        sequence comprising a sequence which is at least 95% identical        to the heavy chain variable region CDR1 sequence of MEDI 8897,        and a heavy chain variable region CDR2 sequence comprising a        sequence which is at least 95% identical to the heavy chain        variable region CDR2 sequence of MEDI 8897, and a heavy chain        variable region CDR3 sequence comprising a sequence which is at        least 95% identical to the heavy chain variable region CDR3        sequence of MEDI 8897, and a light chain variable region CDR1        sequence comprising a sequence which is at least 95% identical        to the light chain variable region CDR1 sequence of MEDI 8897,        and a light chain variable region CDR2 sequence comprising a        sequence which is at least 95% identical to the light chain        variable region CDR2 sequence of MEDI 8897, and a light chain        variable region CDR3 sequence comprising a sequence which is at        least 95% identical to the light chain variable region CDR3        sequence of MEDI 8897.

The invention also provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody having a heavy chain variable        region CDR1 sequence which differs by no more than 1 amino acid        from the heavy chain variable region CDR1 sequence of MEDI 8897,        and a heavy chain variable region CDR2 sequence which differs by        no more than 1 amino acid from the heavy chain variable region        CDR2 sequence of MEDI 8897, and a heavy chain variable region        CDR3 sequence which differs by no more than 1 amino acid from        the heavy chain variable region CDR3 sequence of MEDI 8897, and        a light chain variable region CDR1 sequence which differs by no        more than 1 amino acid from the light chain variable region CDR1        sequence of MEDI 8897, and a light chain variable region CDR2        which differs by no more than 1 amino acid from the light chain        variable region CDR2 sequence of MEDI 8897, and a light chain        variable region CDR3 sequence comprising a sequence which which        differs by no more than 1 amino acid from the light chain        variable region CDR3 sequence of MEDI 8897;    -   ii. an ionic excipient (e.g. a salt) as defined anywhere herein;    -   iii. a sugar as defined anywhere herein;    -   iv. one or more buffers as defined anywhere herein; and    -   v. optionally a surfactant as defined anywhere herein        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml) and the ionic excipient is present at a a concentration        of about 50 to about 150 mM and the formulation has a pH of        about 5.5 to about 7.5.

The invention also provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody having the 6 CDRs of MEDI        8897;    -   ii. an ionic excipient (e.g. a salt) as defined anywhere herein;    -   iii. a sugar as defined anywhere herein;    -   iv. one or more buffers as defined anywhere herein; and    -   v. optionally a surfactant as defined anywhere herein        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml) and the ionic excipient is present at a concentration of        about 50 to about 150 mM and the formulation has a pH of about        5.5 to about7.5.

The invention thus provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody having the VH and VL        sequences of MEDI 8897;    -   ii. an ionic excipient (e.g. a salt) as defined anywhere herein;    -   iii. a sugar as defined anywhere herein;    -   iv. one or more buffers as defined anywhere herein; and    -   v. optionally a surfactant as defined anywhere herein        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater and the ionic excipient is present at        a concentration of about 50 to about 150 mM and the formulation        has a pH of about 5.5 to about 7.5.

The invention thus provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody having the full length heavy        and light chain sequences of MEDI 8897;    -   ii. an ionic excipient (e.g. a salt) as defined anywhere herein;    -   iii. a sugar as defined anywhere herein;    -   iv. one or more buffers as defined anywhere herein; and    -   v. optionally a surfactant as defined anywhere herein        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml) and the ionic excipient is present at a concentration of        about 50 to about 150 mM and the formulation has a pH of about        5.5 to about 7.5.

The invention thus provides a formulation comprising:

-   -   i. anti-RSV monoclonal antibody MEDI 8897;    -   ii. an ionic excipient (e.g. a salt) as defined anywhere herein;    -   iii. a sugar as defined anywhere herein;    -   iv. one or more buffers as defined anywhere herein; and    -   v. optionally a surfactant as defined anywhere herein        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml) and the ionic excipient is present at a concentration of        about 50 to about 150 mM and the formulation has a pH of about        5.5 to about 7.5.

The invention provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody;    -   ii. arginine hydrochloride;    -   iii. sucrose;    -   iv. L-histidine/L-histidine hydrochloride monohydrate; and    -   v. polysorbate-80        wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml) and the arginine hydrochloride is present at a        concentration of about 50 to about 150 mM and the formulation        has a pH of about 5.5 to about7.5. In one embodiment, the RSV        monoclonal antibody has the 6 CDRs of MEDI 8897. In one        embodiment, the RSV monoclonal antibody has the VH and VL        sequences of MEDI 8897. In one embodiment, the RSV monoclonal        antibody has the full length heavy and light chain sequences of        MEDI 8897. In one embodiment, the RSV monoclonal antibody is        MEDI 8897.

The invention provides a formulation comprising:

-   -   i. an anti-RSV monoclonal antibody;    -   ii. arginine hydrochloride;    -   iii. sucrose;    -   iv. L-histidine/L-histidine hydrochloride monohydrate; and    -   v. polysorbate-80        wherein the monoclonal antibody is present at a concentration of        about 100 mg/mL and the arginine hydrochloride is present at a        concentration of about 80 mM and the formulation has a pH of        about 6.0. The sucrose preferably has a concentration of about        120 mM. The L-histidine/L-histidine hydrochloride monohydrate        preferably has a concentration of about 30 mM. The polysorbate        preferably has a concentration of between 0.02% and 0.04%, more        preferably the concentration is 0.02%. In one embodiment, the        RSV monoclonal antibody has the 6 CDRs of MEDI 8897. In one        embodiment, the RSV monoclonal antibody has the VH and VL        sequences of MEDI 8897. In one embodiment, the RSV monoclonal        antibody has the full length heavy and light chain sequences of        MEDI 8897. In one embodiment, the RSV monoclonal antibody is        MEDI 8897.

The formulations described herein can also include one or moreadditional excipients, including for example, one or more sugars, salts,amino acids, polyols, chelating agents, emulsifiers and/orpreservatives.

The formulations of the invention preferably are pharmaceuticalformulations.

The present invention provides an isolated monoclonal antibody havinglight chain CDR sequences: CDR-L1 of SEQ ID NO: 3, CDR-L2 of SEQ ID NO:4, CDR-L3 of SEQ ID NO: 5 and heavy chain CDR sequences: CDR-H1 of SEQID NO: 6, CDR-H2 of SEQ ID NO: 7, CDR-H3 of SEQ ID NO: 8. The presentinvention provides an isolated monoclonal antibody having a light chainvariable region sequence of SEQ ID NO: 9 and a heavy chain variableregion sequence of SEQ ID NO: 10. The present invention provides anisolated monoclonal antibody having the three CDRs of light chainvariable region of sequence of SEQ ID NO: 9 and the three CDRs of heavychain variable region sequence of SEQ ID NO: 10. The present inventionprovides an isolated monoclonal antibody having a light chain sequenceof SEQ ID NO: 1 and a heavy chain sequence of SEQ ID NO: 2. Preferably,the antibody is an IgG1 antibody. The present invention provides noveland inventive monoclonal antibodies per se based on novel and inventivemonoclonal antibody MEDI-8897 as disclosed herein. The present inventionprovides a hybridoma capable of expressing an isolated monoclonalantibody according to the present invention. The present inventionprovides a nucleic acid encoding an isolated monoclonal antibodyaccording to the present invention. The present invention provides anexpression vector comprising a nucleic acid according to the presentinvention. The present invention provides a host cell comprising anexpression vector according to the present invention. The presentinvention provides a process for recombinantly producing an isolatedmonoclonal antibody according to the present invention comprisingculturing the host cell under conditions such that the antibody isexpressed. The present invention provides an isolated monoclonalantibody as defined herein for use as a medicament. The presentinvention provides an isolated monoclonal antibody as defined herein foruse in the treatment of a disease. The present invention provides amethod of treating a disease in a subject comprising administering anisolated monoclonal antibody as defined herein to the subject. Thepresent invention provides a pharmaceutical composition comprising anisolated monoclonal antibody as defined herein. The present inventionprovides a pharmaceutical composition as defined herein for use as amedicament. The present invention provides a pharmaceutical compositionas defined herein for use in the treatment of a disease. The presentinvention provides a method of treating a disease in a subjectcomprising administering a pharmaceutical composition as defined hereinto the subject.

The present invention provides a pharmaceutical formulation as describedanywhere herein for use as a medicament.

The present invention provides a pharmaceutical formulation as describedanywhere herein for use in the treatment or prevention of a disease.

The present invention provides a method of treating or preventing adisease in a subject comprising administering a pharmaceuticalformulation as described anywhere herein to the subject. Also providedherein are methods of treating or preventing a disease in a subject byadministering a therapeutically effective amount of a pharmaceuticalformulation as described anywhere herein to the subject.

In one embodiment, the subject is a human. In one embodiment, thesubject is a human under 2 years of age. In one embodiment, the subjectis a premature baby under 6 weeks of age.

In one embodiment, the disease is a lower respiratory tract disease.

In one embodiment, the disease is RSV infection.

BRIEF DESCRIPTIONS OF THE DRAWINGS

FIG. 1 shows the MEDI8897 heavy chain nucleotide sequence andtranslation.

FIG. 2 shows the MEDI8897 light chain nucleotide sequence andtranslation.

FIG. 3 shows MEDI8897 formulation stability over a 3 month period at 5°C., 25° C. and 40° C.

DETAILED DESCRIPTION OF THE INVENTION

Due to the fact that a number of monoclonal antibodies possess a pI thatis close to physiologic pH, i.e. the pH generally desired for humanadministration, difficulties in formulating these monoclonal antibodiesoccur. For such monoclonal antibodies, for the first time, the presentinvention provides motivation to formulate these ‘difficult’ antibodiesas pharmaceuticals. Prior to the present invention, such antibodiesmight have been dismissed from being considered as drug candidatesbecause of the lack of an appropriate formulation strategy forformulating at a commercially useful concentration and within acommercially useful pH range.

The present invention provides a new monoclonal antibody formulation.Suitably, the formulation has a pH that is within 1.0 pH unit below theisoelectric point of the monoclonal antibody.

The invention provides a formulation comprising: (i) an anti-RSVmonoclonal antibody; and (ii) an ionic excipient (e.g. a salt); whereinthe monoclonal antibody is present at a concentration of about 50mg/mlor greater and the ionic excipient is present at a concentration ofbetween 50 and 150 mM and the formulation has a pH of about 5.5 to about7.5.

The invention further provides a formulation comprising: (i) an anti-RSVmonoclonal antibody; and (ii) an ionic excipient (e.g. a salt); whereinthe monoclonal antibody is present at a concentration of about 50mg/mlor greater (e.g., about 50 mg/ml to about 200 mg/ml) and the ionicexcipient is present at a a concentration of about 50 to about 150 mMand the formulation has a pH of about 5.5 to about 7.5; and wherein theaggregation rate of the monoclonal antibody in the formulation isreduced compared to the aggregation rate of the same antibody in thesame formulation but without an ionic excipient.

Aggregation rate can be measured according to standard techniques asdescribed herein. Surprisingly, formulations in accordance with thepresent invention have been shown to have good stability and to havedecreased self-aggregation e.g. to exhibit ≤2.0% aggregation when storedat room temperature for 3 months. The present invention thus providesthe use of an ionic excipient in an antibody formulation for the purposeof increasing stability of the antibody in the formulation. The presentinvention further provides the use of an ionic excipient in an antibodyformulation for the purpose of decreasing self-aggregation of theantibody in the formulation.

Antibody

The formulations of the present invention are particularly useful foranti-RSV antibodies having a low or neutral pI, for example in the rangeabout pH 5.5 to about pH 7.5, about pH 6.0 to about pH 7.5, about pH 6.3to about pH 7.5, or about pH 6.4 to about pH 7.5. The pI of an antibodycan be measured according to standard techniques, for example bycapillary isoelectric focusing (cIEF). The invention thus provides aformulation comprising: (i) a monoclonal antibody having a low orneutral pI; and (ii) an ionic excipient; wherein the monoclonal antibodyis present at a concentration of about 50 mg/ml or greater (e.g., about50 mg/ml to about 200 mg/ml) and the ionic excipient is present at a aconcentration of about 50 to about 150 mM and the formulation has a pHof about 5.5 to about 7.5. The invention thus further provides aformulation comprising: (i) a monoclonal antibody having a low orneutral pI; and (ii) an ionic excipient; wherein the monoclonal antibodyis present at a concentration of about 50mg/m1 or greater and the ionicexcipient is present at a a concentration of about 50 to about 150 mMand the formulation has a pH of about 5.5 to about 7.5; and wherein theaggregation rate of the monoclonal antibody in the formulation isreduced compared to the aggregation rate of the same antibody in thesame formulation but without an ionic excipient.

In one embodiment, the monoclonal antibody has a pI in the range of pH6.4 to pH 7.5.

In one embodiment, the monoclonal antibody is an IgG1 or IgG4 monoclonalantibody. Most preferably, the monoclonal antibody is an IgG1 monoclonalantibody. The invention thus provides a formulation comprising: (i) anIgG1 monoclonal anti-RSV antibody having a low or neutral pI; and (ii)an ionic excipient; wherein the monoclonal antibody is present at aconcentration of about 50 mg/ml or greater (e.g., about 50 mg/ml toabout 200 mg/ml) and the ionic excipient is present at a a concentrationof about 50 to about 150 mM and the formulation has a pH of about 5.5 toabout 7.5. The invention thus further provides a formulation comprising:(i) an IgG1 monoclonal antibody having a low or neutral pI; and (ii) anionic excipient; wherein the monoclonal antibody is present at aconcentration of about 50 mg/l or greater (e.g., about 50 mg/ml to about200 mg/ml) and the ionic excipient is present at a a concentration ofabout 50 to about 150 mM and the formulation has a pH of about 5.5 toabout 7.5; and wherein the aggregation rate of the monoclonal antibodyin the formulation is reduced compared to the aggregation rate of thesame antibody in the same formulation but without an ionic excipient.

The invention is particularly concerned with formulations comprisingantibody MEDI-8897 or variants thereof. In one embodiment, the anti-RSVmonoclonal antibody has a heavy chain variable region CDR1 sequencecomprising a sequence which is at least 70% identical to the heavy chainvariable region CDR1 sequence of MEDI 8897, and a heavy chain variableregion CDR2 sequence comprising a sequence which is at least 70%identical to the heavy chain variable region CDR2 sequence of MEDI 8897,and a heavy chain variable region CDR3 sequence comprising a sequencewhich is at least 70% identical to the heavy chain variable region CDR3sequence of MEDI 8897, and a light chain variable region CDR1 sequencecomprising a sequence which is at least 70% identical to the light chainvariable region CDR1 sequence of MEDI 8897, and a light chain variableregion CDR2 sequence comprising a sequence which is at least 70%identical to the light chain variable region CDR2 sequence of MEDI 8897,and a light chain variable region CDR3 sequence comprising a sequencewhich is at least 70% identical to the light chain variable region CDR3sequence of MEDI 8897.

In another embodiment, the anti-RSV monoclonal antibody has a heavychain variable region CDR1 sequence comprising a sequence which is atleast 80% identical to the heavy chain variable region CDR1 sequence ofMEDI 8897, and a heavy chain variable region CDR2 sequence comprising asequence which is at least 80% identical to the heavy chain variableregion CDR2 sequence of MEDI 8897, and a heavy chain variable regionCDR3 sequence comprising a sequence which is at least 80% identical tothe heavy chain variable region CDR3 sequence of MEDI 8897, and a lightchain variable region CDR1 sequence comprising a sequence which is atleast 80% identical to the light chain variable region CDR1 sequence ofMEDI 8897, and a light chain variable region CDR2 sequence comprising asequence which is at least 80% identical to the light chain variableregion CDR2 sequence of MEDI 8897, and a light chain variable regionCDR3 sequence comprising a sequence which is at least 80% identical tothe light chain variable region CDR3 sequence of MEDI 8897.

In one embodiment, the anti-RSV monoclonal antibody has a heavy chainvariable region CDR1 sequence comprising a sequence which is at least90% identical to the heavy chain variable region CDR1 sequence of MEDI8897, and a heavy chain variable region CDR2 sequence comprising asequence which is at least 90% identical to the heavy chain variableregion CDR2 sequence of MEDI 8897, and a heavy chain variable regionCDR3 sequence comprising a sequence which is at least 90% identical tothe heavy chain variable region CDR3 sequence of MEDI 8897, and a lightchain variable region CDR1 sequence comprising a sequence which is atleast 90% identical to the light chain variable region CDR1 sequence ofMEDI 8897, and a light chain variable region CDR2 sequence comprising asequence which is at least 90% identical to the light chain variableregion CDR2 sequence of MEDI 8897, and a light chain variable regionCDR3 sequence comprising a sequence which is at least 90% identical tothe light chain variable region CDR3 sequence of MEDI 8897.

In one embodiment, the anti-RSV monoclonal antibody has a heavy chainvariable region CDR1 sequence comprising a sequence which is at least95% identical to the heavy chain variable region CDR1 sequence of MEDI8897, and a heavy chain variable region CDR2 sequence comprising asequence which is at least 95% identical to the heavy chain variableregion CDR2 sequence of MEDI 8897, and a heavy chain variable regionCDR3 sequence comprising a sequence which is at least 95% identical tothe heavy chain variable region CDR3 sequence of MEDI 8897, and a lightchain variable region CDR1 sequence comprising a sequence which is atleast 95% identical to the light chain variable region CDR1 sequence ofMEDI 8897, and a light chain variable region CDR2 sequence comprising asequence which is at least 95% identical to the light chain variableregion CDR2 sequence of MEDI 8897, and a light chain variable regionCDR3 sequence comprising a sequence which is at least 95% identical tothe light chain variable region CDR3 sequence of MEDI 8897.

In another embodiment, the anti-RSV monoclonal antibody has a heavychain variable region CDR1 sequence which differs by no more than 1amino acid from the heavy chain variable region CDR1 sequence of MEDI8897, and a heavy chain variable region CDR2 sequence which differs byno more than 1 amino acid from the heavy chain variable region CDR2sequence of MEDI 8897, and a heavy chain variable region CDR3 sequencewhich differs by no more than 1 amino acid from the heavy chain variableregion CDR3 sequence of MEDI 8897, and a light chain variable regionCDR1 sequence which differs by no more than 1 amino acid from the lightchain variable region CDR1 sequence of MEDI 8897, and a light chainvariable region CDR2 which differs by no more than 1 amino acid from thelight chain variable region CDR2 sequence of MEDI 8897, and a lightchain variable region CDR3 sequence comprising a sequence which whichdiffers by no more than 1 amino acid from the light chain variableregion CDR3 sequence of MEDI 8897.

In another embodiment, the anti-RSV monoclonal antibody has the 6 CDRsof MEDI 8897.

In another embodiment, the anti-RSV monoclonal antibody has the 6 CDRsof MEDI 8897 in combination with 70% identity to the framework regionsequences of MEDI 8897.

In another embodiment, the anti-RSV monoclonal antibody has the 6 CDRsof MEDI 8897 in combination with 80% identity to the framework regionsequences of MEDI 8897.

In another embodiment, the anti-RSV monoclonal antibody has the 6 CDRsof MEDI 8897 in combination with 90% identity to the framework regionsequences of MEDI 8897.

In another embodiment, the anti-RSV monoclonal antibody has the 6 CDRsof MEDI 8897 in combination with 95% identity to the framework regionsequences of MEDI 8897.

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 1:

Position Relative to SEQ ID NO. 2 Amino Acid  28 P  30 R  31 N  37 L  61A  81 I  82 H  84 I 106 T

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 2:

Position Relative to SEQ ID NO. 2 Amino Acid  28 P  30 R  31 N  61 A 106T

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 3:

Position Relative to SEQ ID NO. 2 Amino Acid  28 P  30 R  31 N  45 L  61A 106 T

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 4:

Position Relative to SEQ ID NO. 2 Amino Acid  19 K  23 K  28 T  29 F  30S  31 N  45 L  61 A 106 T

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 5:

Position Relative to SEQ ID NO. 2 Amino Acid  28 P 106 T

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 6:

Position Relative to SEQ ID NO. 2 Amino Acid  28 P 106 T 109 R

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 7:

Position Relative to SEQ ID NO. 2 Amino Acid  19 K  23 K  77 S  82 H  98R 106 T

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 8:

Position Relative to SEQ ID NO. 2 Amino Acid  19 K  23 K  82 H 106 T

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 9:

Position Relative to SEQ ID NO. 2 Amino Acid  19 K  23 K  77 S 106 T

In one embodiment, the anti-RSV monoclonal antibody has the 6 CDRs ofMEDI 8897 in combination with the changes to the heavy chain region ofMEDI 8897 selected from those shown below in Table 10:

Position Relative to SEQ ID NO. 2 Amino Acid  19 K  23 K  77 S  82 H 106T

In another embodiment, the anti-RSV monoclonal antibody has the VH andVL sequences of MEDI 8897.

Preferably, the antibody is an IgG1 antibody.

Preferably, the anti-RSV monoclonal antibody defined anywhere herein hasa heavy chain variable region CDR3 sequence ETALVVSETYLPHYFDN (SEQ IDNO: 8).

In one embodiment of the anti-RSV monoclonal antibody defined anywhereherein, the CDR3 of the heavy chain does not comprise the sequenceETALVVSTTYLPHYFDN. Preferably, any variant heavy chain variable regionCDR3 sequences (i.e variants of SEQ ID NO: 8) in the anti-RSV monoclonalantibody defined anywhere herein retain E at the position marked by *:ETALVVS*TYLPHYFDN. Preferably, any variant heavy chain variable regionCDR3 sequences (i.e variants of SEQ ID NO: 8) in the anti-RSV monoclonalantibody defined anywhere herein do not have T at the position marked by*: ETALVVS*TYLPHYFDN.

In an embodiment the anti-RSV monoclonal antibody has a modified Fcregion wherein one or more amino acids has been inserted, deleted orsubstituted so as to increase the half-life of the antibody. In anembodiment, the anti-RSV monoclonal antibody has three amino acidsubstitutions (M252Y/S254T/T256E; called YTE) in the CH2 region of theFc domain.

In another embodiment, the anti-RSV monoclonal antibody has the fulllength heavy and light chain sequences of MEDI 8897. Anti-RSV antibodiesinclude antibody functional parts, e.g., antibodies or antigen-bindingfragments, variants, or derivatives thereof. Anti-RSV antibodies furtherinclude, but are not limited to, polyclonal, monoclonal, human,humanized, or chimeric antibodies, single chain antibodies, bispecificantibodies, epitope-binding fragments, e.g., Fab, Fab′ and F(ab′)2, Fd,Fvs, single-chain Fvs (scFv), single-chain antibodies, disulfide-linkedFvs (sdFv), fragments comprising either a VL or VH domain, fragmentsproduced by a Fab expression library. ScFv molecules are known in theart and are described, e.g., in U.S. Pat. No. 5,892,019. Immunoglobulinor antibody molecules encompassed by this disclosure can be of any type(e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3,IgG4, IgA1 and IgA2) or subclass of immunoglobulin molecule.

Antibody Concentration

Suitably, the monoclonal antibody is present in the formulationsdescribed herein at a concentration of about 50 mg/ml to about 300mg/ml, about 50 mg/ml to about 200 mg/ml, about 100 mg/ml to about 200mg/ml, about 100 mg/ml to about 165 mg/ml, about 100 mg/ml to about 150mg/ml, or about 50 mg/ml, about 75 mg/ml, about 100 mg/ml, about 105mg/ml, about 110 mg/ml, about 115 mg/ml, about 120 mg/ml, about 125mg/ml, about 130 mg/ml, about 135 mg/ml, about 140 mg/ml, about 145mg/ml, about 150 mg/ml, about 155 mg/ml, about 160 mg/ml, about 165mg/ml, about 170 mg/ml, about 175 mg/ml, about 180 mg/ml, about 185mg/ml, about 190 mg/ml, about 195 mg/ml, or about 200 mg/ml, includingvalues and ranges within these ranges.

Suitably, the monoclonal antibody is present in the formulationsdescribed herein at a concentration of about 100 mg/ml to about 165mg/ml. Suitably, the monoclonal antibody is present in the formulationsdescribed herein at a concentration of about 100 mg/ml.

pH

Suitably, the formulations described herein have a pH in the range ofabout pH 5.5 to about pH 6.5 in order to provide near optimal or optimalchemical stability (hydrolysis, deamidation, isomerization). In oneembodiment, the formulations described herein have a pH in the range ofabout pH 5.7 to about pH 6.3. In one embodiment, the formulationsdescribed herein have a pH in the range of about pH 5.7 to about pH 6.1.Preferred formulations have a pH of about 5.8. Other preferredformulations have a pH of about 6.0.

Suitably, the formulations described herein have a pH in the range ofabout pH 5.5 to about pH 6.0, about pH 5.7 to about pH 6.0, or about pH5.5, about pH 5.6, about pH 5.7, about pH 5.8, about pH 5.9, about pH6.0, about pH 6.1, about pH 6.2, about pH 6.3, about pH 6.4, or about pH6.5. In embodiments, the pH of the formulations provided herein is 5.7to 6.0, more suitably the formulations have a pH of about 5.8.

A formulation pH close to about pH 7.4 also can be desirable forinjection site tolerability.

Ionic Excipient

Exemplary ionic excipients for use in the formulations include salts andcharged amino acids. The ionic excipient might comprise a combination ofa salt and charged amino acid.

Exemplary charged amino acids include arginine and lysine.

Exemplary salts include salts of charged amino acids, for example,succinate, acetate, and sulfate salts of arginine and lysine.

Further, exemplary salts are those described herein including, but notlimited to, sodium chloride, as well as other salts with sodium,potassium, calcium, magnesium and the like, such as chlorides,carbonates, sulphates, acetates, gluconates, lactates, malates, andother auxiliaries and the like which are customary in the field ofparenteral administration. Suitably the salt is selected from sodiumchloride (NaCl), lysine hydrochloride and arginine hydrochloride. In oneembodiment, the salt is NaCl. In another embodiment, the salt isarginine hydrochloride.

The concentration of the ionic excipient, suitably salt, in thepharmaceutical formulations described herein is generally in the rangeof about 50 mM to about 300 mM, more suitably about 50 mM to about 200mM, about 50 mM to about 150 mM, about 50 mM to about 100 mM, about 60mM to about 80 mM, or about 50 mM, about 55 mM, about 60 mM, about 65mM, about 70 mM, about 75 mM, about 80 mM, about 85 mM, about 90 mM,about 95 mM or about 100 mM, including any ranges or values within theseranges. In one embodiment, the ionic excipient is present at aconcentration of about 50 mM to about 125 mM.

In one embodiment, the ionic excipient is present at a concentration ofabout 50 mM to about 100 mM.

In one embodiment, the ionic excipient is present at a concentration ofabout 75 mM to about 100 mM.

In suitable embodiments, the salt is NaCl, for example at aconcentration of about 50 mM to about 100 mM, suitably at aconcentration of about 70 mM.

In suitable embodiments, the salt is arginine hydrochloride, for exampleat a concentration of about 50 mM to about 100 mM, suitably at aconcentration of about 80 mM.

Buffers

The formulations described herein suitably comprise one or more buffers.As used herein, “buffer” refers to an excipient for maintaining the pHof a formulation.

Exemplary buffers for use in the formulations provided herein include,but are not limited to histidine, histidine hydrochloride (histidineHCl), sodium succinate, sodium acetate, sodium acetate/acetic acid,sodium phosphate, citrate, phosphate, succinate, glycine, and acetate.In one embodiment, the buffer for use in the formulations describedherein is sodium acetate/acetic acid. In one embodiment, the one or morebuffers is a buffer comprising histidine. In one embodiment, the one ormore buffers are selected from a buffer comprising histidine succinate,histidine acetate, histidine citrate, histidine chloride or histidinesulfate. In one embodiment, the one or more buffers is histidine,histidine hydrochloride, or a combination thereof (histidine/histidinehydrochloride). In one embodiment, the one or more buffers isL-histidine/L-histidine hydrochloride monohydrate.

The concentration of a buffer, suitably sodium acetate/acetic acid, inthe pharmaceutical formulations described herein is generally in therange of about 10 mM to about 100 mM, more suitably about 15 mM to about80 mM, about 25 mM to about 75 mM, about 30 mM to about 60 mM, about 40mM to about 60 mM, about 40 mM to about 50 mM, or about 15 mM, about 20mM, about 25 mM, about 30 mM, about 35 mM, about 40 mM, about 45 mM,about 50 mM, about 55 mM, about 60 mM, about 65 mM, about 70 mM or about75 mM, including any ranges or values within these ranges.

In one embodiment, the one or more buffers is L-histidine/L-histidinehydrochloride monohydrate, for example at a concentration of about 10 mMto about 50 mM, suitably at a concentration of about 30 mM.

The pH of the buffer is preferably in the range of pH5.5 to pH6.0.

It will be understood that a buffer may, itself, be an ionic excipient.Thus, in one embodiment, the buffer is the ionic excipient. In thisembodiment, the concentration of the buffer should be above 50 mM i.e.in line with the concentration of the ionic excipient disclosed herein.Preferable concentrations for the buffer in this embodiment are asdiscussed anywhere herein in relation to the ionic excipient.

Put another way, in one embodiment, the ionic excipient also acts as abuffer in the formulation. In this embodiment, an additional buffer mayor may not be present.

Sugars and Surfactants

The formulations described herein suitably comprise a sugar, forexample, but not limited to, trehalose, lactose, mannitol, melibiose,melezitose, raffinose, mannotriose, stachyose and sucrose. In otherembodiments, a polyol such as trihydric or higher molecular weight sugaralcohols, e.g. glycerin, dextran, erythritol, glycerol, arabitol,xylitol, sorbitol, and mannitol, can be used. Examples of reducingsugars include, but are not limited to, glucose, maltose, maltulose,iso-maltulose and lactulose. Examples of non-reducing sugars include,but are not limited to, trehalose, non-reducing glycosides ofpolyhydroxy compounds selected from sugar alcohols and other straightchain polyalcohols. Examples of sugar alcohols include, but are notlimited to, monoglycosides, compounds obtained by reduction ofdisaccharides such as lactose, maltose, lactulose and maltulose. Theglycosidic side group can be either glucosidic or galactosidic.Additional examples of sugar alcohols include, but are not limited to,glucitol, maltitol, lactitol and iso-maltulose. In one embodiment, thesugar is selected from the group consisting of trehalose, lactose,mannitol, raffinose and sucrose. In specific embodiments, trehalose isused as a sugar in the formulations described herein. In specificembodiments, sucrose is used as a sugar in the formulations describedherein.

Suitably, the amount of sugar, for example trehalose, in a formulationdescribed herein is about 1% (w/v) to about 10% (w/v). Unless otherwisenoted, percentage of a component (%) is used herein indicate aweight/volume (w/v) %. In exemplary embodiments, the amount of sugar ina pharmaceutical formulation described herein is about 1% (w/v) to about8% (w/v), or about 2% (w/v) to about 6% (w/v), about 2% (w/v) to about5% (w/v), about 3% (w/v) to about 5% (w/v), or about 1% (w/v), about 2%(w/v), about 3% (w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v),about 7% (w/v), about 8% (w/v), about 9% (w/v), or about 10% (w/v),including any values and ranges within these ranges.

The formulations described herein suitably comprise a surfactant.

The term “surfactant” as used herein refers to organic substances havingamphipathic structures; namely, they are composed of groups of opposingsolubility tendencies, typically an oil- soluble hydrocarbon chain and awater-soluble ionic group. Surfactants can be classified, depending onthe charge of the surface-active moiety, into anionic, cationic, andnonionic surfactants. Surfactants are often used as wetting,emulsifying, solubilizing, and dispersing agents for variouspharmaceutical formulations and preparations of biological materials.Pharmaceutically acceptable surfactants like polysorbates (e.g.polysorbates 20, 40, 60 or 80); polyoxamers (e.g. poloxamer 188);Triton; sodium octyl glycoside; lauryl-, myristyl-, linoleyl- , orstearyl-sulfobetaine; lauryl-, myristyl-, linoleyl- orstearyl-sarcosine; linoleyl-, myristyl-, or cetyl-betaine;lauroamidopropyl-, cocamidopropyl-, linoleamidopropyl-,myristamidopropyl-, palmidopropyl-, or isostearamidopropyl-betaine (e.g.lauroamidopropyl); myristamidopropyl-, palmidopropyl-, orisostearamidopropyl-dimethylamine; sodium methyl cocoyl-, or disodiummethyl oleyl-taurate; and the MONAQUA™ series (Mona Industries, Inc.,Paterson, N. J.), polyethyl glycol, polypropyl glycol, and copolymers ofethylene and propylene glycol (e.g. Pluronics, PF68 etc), can be used inthe pharmaceutical formulations described herein. Suitably thesurfactant is a polysorbate, including for example, polysorbate-20,polysorbate-40, polysorbate-60, and polysorbate-80. In one embodiment,the surfactant is polysorbate-80.

Suitably, the formulations described herein comprise a surfactant(suitably polysorbate-80) at about 0.001% to about 0.5% (w/v), moresuitably about 0.002% to about 0.1% of a surfactant, for example about0.01% to about 0.2%, about 0.02% to about 0.1%, about 0.02% to about0.07%, about 0.03% to about 0.06%, about 0.04% to about 0.06%, or about0.02%, about 0.025%, about 0.03%, about 0.035%, about 0.04%, about0.045%, about 0.05%, about 0.055%, about 0.060%, about 0.065%, about0.07%, about 0.075%, about 0.08%, about 0.085%, about 0.09%, about0.095%, or about 0.1% of a surfactant, including any ranges or valueswithin these ranges.

The formulations described herein suitably comprise a surfactant and asugar. The formulations described herein suitably comprise a surfactantand one or more buffers. The formulations described herein suitablycomprise a sugar and one or more buffers. The formulations describedherein suitably comprise a surfactant, a sugar, and one or more buffers.

The formulations described herein can also include one or moreadditional excipients, including for example, one or more sugars, salts,amino acids, polyols, chelating agents, emulsifiers and/orpreservatives.

Pharmaceutical Use

The formulations of the invention preferably are pharmaceuticalformulations. Suitably, the pharmaceutical formulations described hereinare “pharmaceutically acceptable,” and thus would meet the necessaryapproval requirements required by a regulatory agency of the Federal ora state government, or listed in the U.S. Pharmacopeia, EuropeanPharmacopeia, or other generally recognized pharmacopeia, so as to beused in animals, and more particularly in humans.

The present invention provides a pharmaceutical formulation as describedanywhere herein for use as a medicament. The present invention providesa pharmaceutical formulation as described anywhere herein for use in thetreatment of a disease. The present invention provides a method oftreating a disease in a subject comprising administering apharmaceutical formulation as described anywhere herein to the subject.Also provided herein are methods of treating a subject by administeringa therapeutically effective amount of a pharmaceutical formulation asdescribed anywhere herein to the subject.

As used herein, the term “subject” includes any human or nonhumananimal. The term “nonhuman animal” includes all vertebrates, forexample, but not limited to, mammals and non-mammals, such as nonhumanprimates, sheep, dogs, cats, horses, cows, chickens, amphibians,reptiles, etc. In one embodiment, the subject is a human.

The present invention provides a method of treating or preventing adisease in a subject comprising administering a pharmaceuticalformulation as described anywhere herein to the subject. Also providedherein are methods of treating or preventing a disease in a subject byadministering a therapeutically effective amount of a pharmaceuticalformulation as described anywhere herein to the subject.

In one embodiment, the subject is a human. In one embodiment, thesubject is a human under 2 years of age. In one embodiment, the subjectis a premature baby under 6 weeks of age.

In embodiments, the formulation is administered to a subjectsubcutaneously or by injection.

Suitably, the formulations are a liquid formulation or a frozenformulation.

Also provided herein are methods of preparing a pharmaceuticalformulation comprising preparing a pharmaceutical formulation asdescribed herein, and suitably loading the pharmaceutical formulationinto a syringe to form a pre-filled syringe.

Suitably, the pharmaceutical formulations described herein are preparedin sterile water, or are resuspended in sterile water for injection atthe desired volume.

In exemplary embodiments, the pharmaceutical formulations have a volumeof about 0.1 mL to about 20.0 mL, more suitably about 0.5 mL to about15.0 mL, about 0.5 mL to about 12.0 mL, about 1.0 mL to about 10.0 mL,about 1.0 mL to about 5.0 mL, about 1.0 mL to about 2.0 mL or about 0.5mL, about 0.6 mL, about 0.7 mL, about 0.8 mL, about 0.9 mL, about 1.0mL, about 1.1 mL, about 1.2 mL, about 1.3 mL, about 1.4 mL, about 1.5mL, about 1.6 mL, about 1.7 mL, about 1.8 mL, about 1.9 mL, about 2.0mL, about 2.1 mL, about 2.2 mL, about 2.3 mL, about 2.4 mL, about 2.5mL, about 2.6 mL, about 2.7 mL, about 2.8 mL, about 2.9 mL, or about 3.0mL, including any ranges or values within these ranges.

While in suitable embodiments, the pharmaceutical formulations describedherein are liquid formulations, i.e., pharmaceutical formulationsprepared in sterile water or water for injection (WFI), thepharmaceutical formulations can also be frozen formulations orpreviously lyophilized formulations.

The present invention also provides a lyophilized cake which is capableof being reconstituted using only sterile water into a formulationaccording to the invention as described herein. It will be understoodthat the ratio of antibody: ionic excipient will be the same in thelyophilized cake as in the post-lyophilized formulation. In oneembodiment, the ratio of antibody: ionic excipient is in the range 450:1to 40:1. Where the formulation has been lyophilized, the concentrationsprovided herein for the formulation are the post-reconstitutionconcentrations and thus are the concentrations in the so-called ‘drugproduct’. By way of example, if a half-reconstitution strategy is used(where half the volume of water removed during lyophilization isreturned during reconstitution), then after reconstitution, theconcentration of the antibody will be twice what it was prior tolyophilization i.e. twice what is was in the so-calledpre-lyophilization ‘drug-substance’ composition. It will therefore beunderstood that the present invention further provides a compositioncapable of being lyophilized to form a lyophilized cake, wherein thelyophilized cake is capable of being reconstituted using only sterilewater into a formulation according to the invention as described herein.Suitable reconstitution strategies will be known to those skilled in theart. In embodiments, it is desirable to prepare frozen formulations byproviding a liquid pharmaceutical formulation as described herein, andfreezing the formulation under appropriate conditions. For example, thefrozen formulations can be provided by freezing the liquid formulationsto less than 0° C., more suitably to about −20 ° C., about −40° C.,about −60 ° C., or suitably to about −80° C. The pharmaceuticalformulations are also suitably prepared as liquid formulations andstored about 2° C. to about 8° C., or about 2° C., about 3° C., about 4°C., about 5° C., about 6° C., about 7° C. or about 8° C.

Suitable protocols and methods for preparing lyophilized pharmaceuticalformulations from liquid and/or frozen formulations are known in theart.

Stability of Formulations

In exemplary embodiments, the formulations described herein are stablefor extended periods of storage at room temperature or at a temperaturerange of about 2° C. to about 8° C., suitably about 5° C. As usedherein, room temperature is generally in the range of about 22° C. toabout 25° C. Suitably the pharmaceutical formulations are stable afterstorage at about 2° C. to about 8° C. (e.g. 5° C.) for at least six (6)months. As used herein, the term “stable” for a period of storage (or“stability”) is used to indicate that the formulations resistaggregation, degradation, half antibody formation, and/or fragmentation.The stability of the monoclonal antibodies can be assessed by degrees ofaggregation, degradation, half antibody formation or fragmentation, asmeasured by high performance size exclusion chromatography (HPSEC),static light scattering (SLS), Fourier Transform Infrared Spectroscopy(FTIR), circular dichroism (CD), urea unfolding techniques, intrinsictryptophan fluorescence, differential scanning calorimetry, and/or ANSbinding techniques, compared to a reference.

The overall stability of a pharmaceutical formulation comprisingmonoclonal antibodies can be assessed by various immunological assaysincluding, for example, ELISA and radioimmunoassay using isolatedantigen molecules.

The phrase “low to undetectable levels of aggregation” as used hereinrefers to pharmaceutical formulations containing no more than about 5%,no more than about 4%, no more than about 3%, no more than about 2%, nomore than about 1%, or no more than about 0.5% aggregation by weight ofprotein as measured by high performance size exclusion chromatography(HPSEC) or static light scattering (SLS) techniques. Suitably, thepharmaceutical formulations exhibit ≤5.0% aggregation, more suitably≤4.0% aggregation, ≤3.0% aggregation, ≤2.0% aggregation, ≤1.0%aggregation, or 0.5% aggregation. Suitably, the liquid pharmaceuticalformulations and/or frozen pharmaceutical formulations exhibit ≤5.0%aggregation, more suitably ≤4.0% aggregation, ≤3.0% aggregation, ≤2.0%aggregation, ≤1.0% aggregation, or 0.5% aggregation.

The term “low to undetectable levels of fragmentation” as used hereinrefers to pharmaceutical formulations containing equal to or more thanabout 80%, about 85%, about 90%, about 95%, about 98%, or about 99% ofthe total monoclonal antibody, for example, in a single peak asdetermined by HPSEC, or reduced Capillary Gel Electrophoresis (rCGE),representing the non-degraded monoclonal antibody, or a non-degradedfragment thereof, and containing no other single peaks having more thanabout 5%, more than about 4%, more than about 3%, more than about 2%,more than about 1%, or more than about 0.5% of the total monoclonalantibody. Fragmentation may be measured suitably in IgG4 monoclonalantibodies.

Without wishing to be bound by theory, it is thought that decreasedself-aggregation is due to improved colloidal stability, as evidenced byincreased kD value.

In exemplary embodiments, the formulations described herein have reducedopalescence and decreased phase separation as visual observation, lightscattering, nephelometry and turbidimetric methods.

Further embodiments, features, and advantages of the embodiments, aswell as the structure and operation of the various embodiments, aredescribed in detail below with reference to accompanying drawings.

EXAMPLES Example 1 IgG1 Formulation

MEDI8897 is a human IgG1κ- YTE monoclonal antibody directed againstRSV-F protein. Three amino acid substitutions (M252Y/S254T/T256E; calledYTE) in the CH2 region of the Fc domain were introduced to increase theserum half-life of MEDI8897. Sequence information for MEDI8897 isprovided in FIGS. 1 and 2 MEDI8897 pI was measured by cIEF to be 6.4-6.7with the main peak at 6.4. The pI overlaps with the formulation bufferrange (5.5-6.5) suggesting potential issues with manufacturing,formulation and storage stability.

MEDI8897 thermal stability was measured by differential scanningcalorimetry. Tm1 was found to be 61° C. while Tm2 was 82° C. Tm1 of 61°C. meets the CDTP criteria of Tm1>50° C.

Stability Summary

Upon receipt of MEDI8897 in the default developability buffer (25 mMHistidine, 7% sucrose, pH 6.0), phase separation was observed at 2 to 8°C. The supernatant layer had a protein concentration of 75 mg/ml whilethe bottom layer was 125 mg/ml. Upon equilibration at 25° C. the twodistinct phases disappeared and only one single phase was observed. Thephase separation at 2 to 8° C. was thought to be due to the pI ofMEDI8897 which is close to the formulation pH of 6.0. A scouting studywas initiated to find a more appropriate formulation buffer for MEDI8897stability assessment, targeting a condition which maintained solubilityand prevented phase separation of MEDI8897 at 100 mg/ml.

Formulating in the default developability buffer (25 mM histidine, 7%sucrose) at pH's<5.9 or >6.7 mitigated phase separation. Addition of 75mM NaCl to the developability buffer between pH 5.0 and 6.7 alsomitigated phase separation. Finally, acetate and phosphate buffers at pHvalues away from the pI also mitigated phase separation. Based on thesescreening studies and previous knowledge of mAb's with pI's within theformulation space, an alternate developability buffer (25 mM His/HisHCl,75 mM NaCl, 4% Sucrose, 0.02% PS80, pH 6.0) was selected for evaluation.

kD Studies

For the first kD screen, all samples were evaluated in 25 mM HistidinepH 5.5 base buffer from 2-10 mg/ml at 25° C. This buffer was chosen inlieu of pH 6.0 because MEDI8897 is more soluble at pH 5.5, facilitatingDLS measurements which are sensitive to insoluble particles. Ionicexcipients including arginine-HCl, lysine-HCl and NaCl were evaluated at10, 25, 50, 75 and 100 mM concentrations. In addition, proline, alanine,Na₂SO₄ and histidine were evaluated at the 100 mM concentration only.Finally, 2, 4, and 6% sucrose were evaluated to determine if sucroseinfluences protein-protein interactions. All conditions were compared toa buffer control (25 mM Histidine pH 5.5).

The control samples showed distinct protein-protein interactions, withthe hydrodynamic radius increasing from 6.2 to 7.8 nm from 2-10 mg/ml.Arginine-HCl, lysine-HCl and NaCl showed reduction of protein-proteininteractions starting at 25 mM concentrations as evidenced by noincrease in hydrodynamic size over the 2-10 mg/ml concentration range.No additional effects were seen between 25 and 100 mM. At 100 mMconcentration, proline and alanine showed PPI similar to the controlwhile Na₂SO₄ and Histidine mitigated PPI. Finally, sucrose concentrationshowed no impact on PPI. This data illustrates that charged excipients(Arg-HCl, Lys-HCl, Histidine and Na₂SO₄) mitigate protein-proteininteractions while neutral excipients (sucrose, proline, alanine) do notmitigate PPI. Therefore, addition of ionic excipients at pH 5.5 reducedphase separation at 100 mg/ml.

40° C. Stability Evaluation

Based on kD screening, several conditions were selected for 40° C.stability evaluation. Table 11 summarizes the formulation conditions and1 month degradation rates seen at 40° C.

TABLE 11 40° C. Stability Rates, Formulation Screen 1- ExcipientScreening Number Excipient Conc (mM) % Mon/mo % Agg/mo % Frag/mo  1 NaCl 25 −5.9 4.2 1.8  2 NaCl  75 −6.1 4.1 1.9  3 NaCl  95 −5.4 3.5 1.9  4NaCl 120 −5.4 3.5 1.9  5 Arg-HCl  25 −5.4 3.5 1.8  6 Arg-HCl  75 −4.82.8 2.0  7 Arg-HCl  95 −4.5 2.6 1.9  8 Arg-HCl 120 −4.8 2.8 2.0  9Lys-HCl  25 −5.7 3.9 1.9 10 Lys-HCl  75 −5.0 2.7 2.3 11 Lys-HCl  95 −5.13.1 2.0 12 Lys-HCl 120 −4.9 2.9 2.0 Base buffer for this study was 25 mMHistidine pH 6.0

This study illustrates that arginine and lysine are more stabilizingthan NaCl. In addition, 75 mM and above appears to stabilize againstaggregation. Based on this study, arginine was selected as the moststabilizing lyo-friendly excipient and was moved forward to the next setof studies.

Drug Product Stability on Final Lyo Cycle/Representative Material

Stability was evaluated in formulation sciences to complement theIND-enabling stability studies as this was the first representativematerial to complete the lyophilization step. Three months of data wascollected for the post reconstitution formulation of 100 mg/ml in 30 mML-histidine/L-histidine hydrochloride monohydrate, 80 mM L-argininehydrochloride, 120 mM sucrose, 0.04% (w/v) polysorbate 80, pH 6.0.Results are shown in FIG. 3. Storage at 2-8° C. showed virtually nochange during the 3 month period, confirming the suitability of theformulation and lyo cycle for clinical use. These data thus demonstratethat the formulation provides appropriate stability and solubility andis suitable as a cycle 1 formulation.

TABLE 12 Drug Product Stability 3 Month Data Summary HIAC HIAC ReconTemperature (≥10 μm) (≥25 μm) Bioassay Time VI KF 2-8° C. 216 108 97% 2min <STD1 1.3%  25° C. 522 90 97% 3 min <STD1 1.4%  40° C. 126 0 90% 3min <STD2 1.7%

All documents, patents, journal articles and other materials cited inthe present application are hereby incorporated by reference.

Although the present invention has been fully described in conjunctionwith several embodiments thereof with reference to the accompanyingdrawings, it is to be understood that various changes and modificationscan be apparent to those skilled in the art. Such changes andmodifications are to be understood as included within the scope of thepresent invention as defined by the appended claims, unless they departthere from.

The invention may be further defined by reference to the followingnumbered paragraphs.

-   Paragraph 1. A formulation comprising:    -   i. An anti-RSV monoclonal antibody; and    -   ii. an ionic excipient;    -   wherein the monoclonal antibody is present at a concentration of        about 50 mg/ml or greater (e.g., about 50 mg/ml to about 200        mg/ml, to about 175 mg/ml, to about 165 mg/ml, to about 150 mg/1        or to about 125mg/ml) and the ionic excipient is present at a a        concentration of about 50 to about 150 mM and the formulation        has a pH of about 5.5 to about 7.5.-   Paragraph 2. A formulation according to paragraph 1, wherein the    monoclonal antibody has a pI in the range of pH 6.4 to pH 7.5.-   Paragraph 3. A formulation according to paragraph 1 or paragraph 2,    wherein the monoclonal antibody has a pI in the range of about pH    6.4.-   Paragraph 4. A formulation according to any one of the preceding    paragraphs, wherein the monoclonal antibody is an IgG1 monoclonal    antibody.-   Paragraph 5. A formulation according to any one of the preceding    paragraphs, wherein the monoclonal antibody has light chain CDR    sequences:-   CDR-L1 of SEQ ID NO: 3-   CDR-L2 of SEQ ID NO: 4-   CDR-L3 of SEQ ID NO: 5    and heavy chain CDR sequences:-   CDR-H1 of SEQ ID NO: 6-   CDR-H2 of SEQ ID NO: 7-   CDR-H3 of SEQ ID NO: 8.-   Paragraph 6. A formulation according to any one of the preceding    paragraphs, wherein the monoclonal antibody has a light chain    variable region sequence of SEQ ID NO: 9 and a heavy chain variable    region sequence of SEQ ID NO: 10.-   Paragraph 7. A formulation according to any one of the preceding    paragraphs, wherein the monoclonal antibody has a light chain    sequence of SEQ ID NO: 1 and a heavy chain sequence of SEQ ID NO: 2.-   Paragraph 8. A formulation according to any one of the preceding    paragraphs, wherein the monoclonal antibody is present in the    formulation at a concentration of about 100 mg/ml to about 165    mg/ml.-   Paragraph 9. A formulation according to paragraph 8, wherein the    monoclonal antibody is present in the formulation at a concentration    of about 100 mg/ml.-   Paragraph 10. A formulation according to any one of the preceding    paragraphs, wherein the formulation has a pH in the range of about    pH 5.7 to about pH 6.1.

Paragraph 11. A formulation according to paragraph 10, wherein theformulation has a pH of about pH 6.0.

-   Paragraph 12. A formulation according to any one of the preceding    paragraphs, wherein the ionic excipient is a salt.-   Paragraph 13. A formulation according to paragraph 12, wherein the    salt is arginine hydrochloride.-   Paragraph 14. A formulation according to any one of the preceding    paragraphs, wherein the ionic excipient is present at a    concentration of about 75 mM to about 100 mM.-   Paragraph 15. A formulation according to paragraph 14, wherein the    ionic excipient is present at a concentration of about 80 mM.-   Paragraph 16. A formulation according to any one of the preceding    paragraphs, wherein the formulation further comprises a sugar.-   Paragraph 17. A formulation according to paragraph 16, wherein the    sugar is sucrose.-   Paragraph 18. A formulation according to any one of paragraphs 16 to    17, wherein the sugar is present at a concentration of about 100 mM    to about 140 mM.-   Paragraph 19. A formulation according to paragraph 18, wherein the    sugar is present at a concentration of about 120 mM.-   Paragraph 20. A formulation according to any one of the preceding    paragraphs, wherein the formulation further comprises one or more    buffers.-   Paragraph 21. A formulation according to paragraph 20, wherein the    one or more buffers is selected from histidine, histidine    hydrochloride, and histidine/histidine hydrochloride.-   Paragraph 22. A formulation according to paragraph 21, wherein the    one or more buffers is L-histidine/L-histidine hydrochloride    monohydrate.-   A formulation according to any one of paragraphs 20 to 23, wherein    the one or more buffers is present at a concentration of about 10 mM    to about 50 mM.-   Paragraph 23. A formulation according to paragraph 23, wherein the    one or more buffers is present at a concentration of about 30 mM.-   Paragraph 24. A formulation according to any one of the preceding    paragraphs, wherein the formulation further comprises a surfactant.-   Paragraph 25. A formulation according to paragraph 25, wherein the    surfactant is a polysorbate.-   Paragraph 26. A formulation according to paragraph 26, wherein the    surfactant is polysorbate-80.-   Paragraph 27. A formulation according to any one of paragraphs 25 to    27, wherein the surfactant is present in the formulation at a    concentration from about 0.001% (w/v) to about 0.07% (w/v).-   Paragraph 28. A formulation according to paragraph 28, wherein the    surfactant is present in the formulation at a concentration of about    0.02% (w/v).-   Paragraph 29. A formulation according to any one of the preceding    paragraphs, wherein the formulation further comprises one or more    additional excipients, including for example, one or more sugars,    salts, amino acids, polyols, chelating agents, emulsifiers and/or    preservatives.-   Paragraph 30. A formulation according to any one of paragraphs 1 to    29, which is a pharmaceutical formulation.-   Paragraph 31. A pharmaceutical formulation according to paragraph 30    for use as a medicament.-   Paragraph 32. A pharmaceutical formulation according to paragraph 31    for use in the treatment of a disease.-   Paragraph 33. A method of treating or preventing a disease in a    subject comprising administering a pharmaceutical formulation    according to paragraph 31 to the subject.-   Paragraph 34. An isolated monoclonal antibody having light chain CDR    sequences:-   CDR-L1 of SEQ ID NO: 3-   CDR-L2 of SEQ ID NO: 4-   CDR-L3 of SEQ ID NO: 5    and heavy chain CDR sequences:-   CDR-H1 of SEQ ID NO: 6-   CDR-H2 of SEQ ID NO: 7-   CDR-H3 of SEQ ID NO: 8.-   Paragraph 35. An isolated monoclonal antibody according to paragraph    35, wherein the monoclonal antibody has a light chain variable    region sequence of SEQ ID NO: 9 and a heavy chain variable region    sequence of SEQ ID NO: 10.-   Paragraph 36. An isolated monoclonal antibody according to paragraph    35 or paragraph 36, wherein the monoclonal antibody has a light    chain sequence of SEQ ID NO: 1 and a heavy chain sequence of SEQ ID    NO: 2.-   Paragraph 37. An isolated monoclonal antibody according to any one    of paragraphs 35 to 37, wherein the antibody is an IgG1 antibody.-   Paragraph 38. A pharmaceutical composition comprising an isolated    antibody as defined in any one of paragraphs 35 to 38.-   Paragraph 39. An isolated monoclonal antibody according to any one    of paragraphs 35 to 38 or a pharmaceutical composition according to    paragraph 39 for use as a medicament.-   Paragraph 40. An isolated monoclonal antibody according to any one    of paragraphs 35 to 38 or a pharmaceutical composition according to    paragraph 39 for use in the treatment of a disease.-   Paragraph 41. A method of treating or preventing a disease in a    subject comprising administering an isolated monoclonal antibody    according to any one of paragraphs 35 to 38 or a pharmaceutical    composition according to paragraph 39 to the subject.-   Paragraph 42. A lyophilized cake capable of being reconstituted    using only sterile water into a formulation as defined in any one of    paragraphs 1 to 31.-   Paragraph 43. A composition capable of being lyophilized to form a    lyophilized cake, wherein the lyophilized cake is capable of being    reconstituted using only sterile water into a formulation as defined    in any one of paragraphs 1 to 31.

What is claimed is:
 1. A formulation comprising: i. an anti-RSVmonoclonal antibody; and ii. an ionic excipient; wherein the monoclonalantibody is present at a concentration of about 50mg/ml or greater andthe ionic excipient is present at a concentration of about 50 to about150 mM and the formulation has a pH of about 5.5 to about 7.5.
 2. Aformulation according to claim 1, wherein the monoclonal antibody has apI in the range of pH 6.4 to pH 7.5.
 3. A formulation according to claim1, wherein the monoclonal antibody has a pI in the range of about pH6.4.
 4. A formulation according to claim 1, wherein the monoclonalantibody has light chain CDR sequences: CDR-L1 of SEQ ID NO: 3 CDR-L2 ofSEQ ID NO: 4 CDR-L3 of SEQ ID NO: 5 and heavy chain CDR sequences:CDR-H1 of SEQ ID NO: 6 CDR-H2 of SEQ ID NO: 7 CDR-H3 of SEQ ID NO:
 8. 5.A formulation according to claim 1, wherein the monoclonal antibody hasa light chain variable region sequence of SEQ ID NO: 9 and a heavy chainvariable region sequence of SEQ ID NO:
 10. 6. A formulation according toclaim 1, wherein the monoclonal antibody has a light chain sequence ofSEQ ID NO: 1 and a heavy chain sequence of SEQ ID NO:
 2. 7. Aformulation according to claim 1, which is a pharmaceutical formulation.8. A method of treating or preventing a disease in a subject comprisingadministering a pharmaceutical formulation according to claim 7 to thesubject.